Typical allergic dermatitis includes contact dermatitis, atopic dermatitis and the like.
The contact dermatitis is an inflammation of the skin, which is developed by the contact of a substance with the skin. The onset of the disease is seen when, for example, a certain substance, such as plant (e.g., lacquer and the like), cosmetics, detergent, clothes, commercially available external drug and the like, comes into contact with the skin and when the substance irritates beyond the resistance threshold value of the individual or when the individual has been sensitized with the substance in contact. The onset of the contact dermatitis is caused by physicochemical properties of the substance, sensitization activity, contact frequency, disposition of the individual and the like. The disease type includes irritant dermatitis, phototoxic dermatitis, allergic dermatitis, photoallergic dermatitis, contact urticaria, systemic contact-type dermatitis and the like. The clinical symptoms of contact dermatitis include acute eczema accompanied by erythema, edema, papula, vesicle, erosion, itching and the like, and repetition thereof develops eczema accompanying lichenification and infiltration. The mechanism of the onset of these diseases is considered to involve type IV allergic reaction (delayed type allergic reaction) caused by T cell. The type IV allergic reaction is induced by the reaction of sensitized T cell and antigen, which releases lymphokine from the sensitized T cell to cause cytotoxicity and the like, which in turn induces this allergic reaction.
The atopic dermatitis is developed by exogenous disposition, namely, by various antigens, since the subject has an atopic disposition which is hypersensitivity against a certain substance. The clinical symptoms include marked itching, skin hypertrophy, infiltration, lichenification and the like. The mechanism of the onset of this disease has been said to include type I allergic reaction (immediate hypersensitivity) involving IgE, but it is inconclusive. In recent years, type IV allergic reaction has been considered to be responsible for the onset of this disease, and in fact, the clinical symptoms of this disease are extremely similar to the symptoms of the above-mentioned contact dermatitis allegedly caused by type IV allergic reaction.
Currently, anti-histamine agents and steroidal agents have been used as therapeutic agent for contact dermatitis, and these and a part of the so-called antiallergic agents have been mainly used for atopic dermatitis.
Examples of anti-histamine agents include diphenhydramine hydrochloride, mequitazine, promethazine hydrochloride, chlorpheniramine maleate and the like, and they have been mainly used to reduce itchiness.
As the steroidal agents, prednisolone, hydrocortisone butyrate, dexamethasone valerate, betamethasone dipropionate, clobetasol propionate and the like have been used. While these show therapeutic effects, they also cause side effects of induced infection, secondary adrenal cortical insufficiency, diabetes, peptic ulcer, hirsutism, alopecia, pigmentation and the like, and they are remotely desirable therapeutic agents.
As the antiallergic agent, tranilast, ketotifen fumarate, oxatomide, azelastine hydrochloride and the like have been used. None of them shows satisfactory therapeutic effects and they are not used for contact dermatitis.
In general, conventional so-called antiallergic agents, such as tranilast, oxatomide, pemirolast potassium, repirinast, emedastine difumarate, epinastine hydrochloride and the like are either ineffective or fail to show satisfactory therapeutic effects on contact dermnatitis and atopic dermatitis that are considered to be mainly caused by type IV allergic reaction. This is postulated to be due to the inhibitory action of these so-called antiallergic agents only on type I allergic reaction (immediate hypersensitivity), in which IgE is involved, and failure to show type IV allergic reaction-inhibitory action (Kobayashi, K. et al.: Japan. J. Pharmacol. 63, 73-81 (1993), Takemori Omori et al.: Folia Pharmacol. Jpn. 80, 261-270 (1982), Yanagihara, Y. et al.: Japan. J. Pharmacol. 51, 93-100 (1989), Kazuo Takahashi et al.: Folia Pharmacol. Jpn. 88, 245-254 (1986), Tadayulk Saito et al.: Folia Pharmacol. Jpn. 89, 55-62 (1987), Kamei, C. et al.: Arzneim.-Forsch./Drug Res.41(II), 1150-1153).
Hence, a type IV allergic reaction-inhibitory action at the inflammation site is considered to be essential for the treatment of allergic dermatitis, particularly contact dermatitis and atopic dermatitis.
Incidentally, it has been documented that a compound of the formula (I): ##STR2##
wherein R.sup.1 is .alpha.-amino acid residue (ester bond) wherein amino may be substituted by lower alkyl and R.sup.2 and R.sup.3 are each lower alkyloxy or substituted or unsubstituted lower alkyl (hereinafter also referred to as cromoglycic acid derivative (I)), can be used as an antiallergic agent.
In the above-mentioned various situations, the development of a highly safe and highly effective therapeutic agent for allergic dermatitis caused by type IV allergic reaction, particularly a therapeutic agent for contact dermatitis and a therapeutic agent for atopic dermatitis, has been demanded.
It is therefore an object of the present invention to provide a therapeutic agent effective for allergic dermatitis, such as contact dermatitis caused by type IV allergic reaction and atopic dermatitis caused by type IV and type I allergic reactions, which is highly safe and can be administered orally.